Phase III Studies Showed ISENTRESS® in Combination Therapy Provided Significant Viral Load Reductions through 96 Weeks in Treatment-Experienced Patients with Triple-Class Resistant HIV
Merck’s Integrase Inhibitor, ISENTRESS, in Combination with Other HIV Medicines Shown as Effective as Efavirenz in Suppressing Viral Load and Increasing CD4 Cell Counts in Treatment-Naïve HIV-infected Patients with High Levels of Virus, Across Various Populations, in Investigational Study
MONTREAL - In new subgroup analyses of a Phase III study (STARTMRK) that compared Merck & Co., Inc.’s integrase inhibitor ISENTRESS® (raltegravir) to efavirenz [one of the leading antiretrovirals prescribed for previously untreated (treatment-naïve) HIV-infected patients], ISENTRESS was found to be as effective as efavirenz at suppressing viral load and provided improvements in immune system function across a broad spectrum of patient subpopulations through 48 weeks. The use of ISENTRESS in previously untreated HIV-infected patients is an investigational use of the drug. Both medicines were taken in combination with tenofovir/emtricitabine (Poster 573).
In other Phase III studies, BENCHMRK-1 and -2, ISENTRESS in combination with optimized background therapy (OBT) demonstrated greater reductions in viral load compared to placebo plus OBT through 96 weeks of therapy in treatment-experienced patients with triple-class resistant HIV who were failing antiretroviral therapy (Poster 571b).
These results as well as data from three additional studies were presented today at the 16th Conference on Retroviruses and Opportunistic Infections (CROI) in Montreal, Canada.
“As physicians continue to use ISENTRESS in treatment-experienced patients, newly presented longer-term data from BENCHMRK-1 and -2 continue to inspire confidence among clinicians when treating patients that are more advanced in their treatment course. Furthermore, the STARTMRK studies in treatment-naïve patients showed that ISENTRESS may become an important new option for a broader spectrum of patients beginning treatment for HIV infection, if the drug is approved for this use,” said Daniel S. Berger, M.D., clinical associate professor, College of Medicine, University of Illinois at Chicago and medical director of NorthStar Medical Center.
ISENTRESS is the first integrase inhibitor approved for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients with evidence of viral replication with HIV-1 strains resistant to multiple antiretroviral agents. This indication is based on analyses of plasma HIV-1 RNA levels up through 48 weeks in two controlled studies of ISENTRESS. These studies were conducted in clinically advanced, three-class antiretroviral [nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs)] treatment-experienced adults. In these studies the use of other active agents with ISENTRESS is associated with a greater likelihood of treatment response. The safety and efficacy of ISENTRESS have not been established in treatment-naïve adult or pediatric patients.
As with all HIV treatment regimens, ISENTRESS should be used with other active antiviral agents.
Important safety information about ISENTRESS
ISENTRESS does not cure HIV or AIDS and does not prevent passing HIV to others. During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium complex, cytomegalovirus, Pneumocystis jiroveci pneumonia, Mycobacterium tuberculosis or reactivation of varicella zoster virus), which may necessitate further evaluation and treatment.
ISENTRESS demonstrated consistent efficacy in reduction of viral load across various patient groups in STARTMRK study
Results from the STARTMRK subgroup analyses showed that at Week 48 ISENTRESS in combination therapy reduced viral load to undetectable levels (less than 50 copies/mL) in 96 percent of women (47 out of 49) compared with 93 percent of women (42 out of 45) receiving efavirenz in combination therapy.
ISENTRESS was also as effective as efavirenz at reducing viral load in patients whose racial background was either black [89 percent for the regimen with ISENTRESS (24 out of 27) compared with 91 percent for the regimen with efavirenz (20 out of 22)], Asian [91 percent (31 out of 34) vs. 87 percent (26 out of 30)], Hispanic [93 percent (54 out of 58) vs. 86 percent (53 out of 62)] or multiracial [91 percent (31 out of 34) vs. 83 percent (30 out of 36)].
The mean increase in CD4 cell counts at 48 weeks was 170 cells/mm³ for women receiving the ISENTRESS-based treatment compared with 168 cells/mm³ for women receiving the regimen with efavirenz. The mean increase from baseline in CD4 cell counts were consistent in patients with diverse racial background and are as follows for patients receiving the regimen with ISENTRESS compared to patients receiving efavirenz-based therapy, respectively: blacks (163 cells/mm³; n=26 vs. 125 cells/mm³; n=21), Asians (185 cells/mm³; n=32 vs. 152 cells/mm³; n=28), Hispanics (196 cells/mm³; n=58 vs. 150 cells/mm³; n=62) and multiracials (182 cells/mm³; n=34 vs. 168 cells/mm³; n=36).
Of those patients with high baseline viral loads (greater than 100,000 copies/mL), 91 percent of patients receiving the regimen with ISENTRESS reduced viral load to undetectable levels versus 89 percent of patients receiving efavirenz-based therapy. The mean increase in CD4 cell counts for patients with high baseline viral loads (greater than 100,000 copies/mL) was 196 cells/mm³ for patients receiving the regimen with ISENTRESS compared with 192 cells/mm³ for patients receiving the regimen with efavirenz.
In this study, 563 treatment-naïve, HIV-infected patients received either 400 mg ISENTRESS administered orally twice daily in combination with tenofovir/emtricitabine or 600 mg efavirenz dosed orally once daily in combination with the same agents. The primary endpoints were reductions in HIV viral load to less than 50 copies/mL at Week 48 and an evaluation of safety and tolerability. Secondary endpoints included antiretroviral activity as measured by reductions in HIV viral load to less than 400 copies/mL and the change from baseline in CD4 cell counts at Week 48.
Durability and persistent tolerability of ISENTRESS demonstrated through 96 weeks in treatment-experienced patients (BENCHMRK-1 and -2)
Ninety-six week results from two Phase III studies, BENCHMRK-1 and -2 were also presented today. Results from these studies showed that at Week 96, 57 percent of patients (262 out of 460) receiving ISENTRESS plus OBT achieved undetectable viral load (less than 50 copies/mL) versus 26 percent of patients (62 out of 237) receiving placebo plus OBT; p less than 0.001. Additionally, patients receiving the regimen with ISENTRESS experienced significantly greater increases in CD4 cell counts (123 cells/mm³) compared to patients receiving placebo plus OBT (49 cells/mm³) at Week 96; p less than 0.001.
In the BENCHMRK studies, patients received either 400 mg ISENTRESS administered orally twice daily in combination with OBT (n=462) or 400 mg placebo dosed orally twice daily in combination with OBT (n=237). Data demonstrated that ISENTRESS plus OBT provided potent and greater antiretroviral and immunological efficacy compared to placebo plus OBT. Reductions in viral load and immunological efficacy were sustained through Week 96: 57 percent of patients receiving ISENTRESS plus OBT maintained viral suppression to less than 50 copies/mL; up to 79 percent of patients receiving enfuvirtide and darunavir in OBT with ISENTRESS maintained viral suppression to less than 50 copies/mL. There were few discontinuations due to adverse experiences, four percent for ISENTRESS plus OBT versus five percent for placebo plus OBT, respectively. The risk of developing malignancy was comparable between ISENTRESS and the control group.
Exposure-adjusted rates (per 100 patient-years) of the most commonly drug-related clinical adverse events (greater than or equal to 2.0 percent, and of any intensity) in patients receiving ISENTRESS plus OBT compared to those receiving placebo plus OBT were headache (2.7 per 100 patient-years vs. 4.5 per 100 patient-years), nausea (2.3 per 100 patient-years vs. 4.1 per 100 patient-years), diarrhea (1.8 per 100 patient-years vs. 4.5 per 100 patient years), fatigue (1.8 per 100 patient-years vs. 0.7 per 100 patient-years), abdominal distension (1.2 per 100 patient-years vs. 1.5 per 100 patient-years), vomiting (0.8 per 100 patient-years vs. 1.9 per 100 patient-years) and pyrexia (0.5 per 100 patient-years vs. 2.2 per 100 patient-years), respectively.
The rate of cancer in patients receiving ISENTRESS plus OBT in both BENCHMRK-1 and -2 was 3.0 per 100 patient-years, compared with 2.6 per 100 patient-years in those patients receiving placebo plus OBT, resulting in a relative risk of 1.1 (0.5, 3.1). The rate of new or recurrent AIDS-defining conditions was 2.2 per 100 patient-years for the group receiving ISENTRESS versus 4.1 per 100 patient-years for the placebo group, respectively, resulting in a relative risk of 0.5 (0.2, 1.3).
Based on 48-week data from BENCHMRK-1 and -2, the U.S. Food and Drug Administration granted ISENTRESS traditional approval for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients with evidence of viral replication with HIV-1 strains resistant to multiple antiretroviral agents in January 2009.
Additional important safety information about ISENTRESS
Due to rifampin’s potent induction of uridine diphosphate glucoronosyltransferase (UGT) 1A1, the recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin. Caution should be used when coadministering ISENTRESS with other strong inducers of UGT1A1 due to reduced plasma concentrations of ISENTRESS.
The most common adverse reactions of moderate to severe intensity (less than or equal to two percent) which occurred at a higher exposure adjusted rate compared to placebo are headache, nausea, asthenia and fatigue.
Creatine kinase elevations were observed in subjects who received ISENTRESS. Myopathy and rhabdomyolysis have been reported; however, the relationship of ISENTRESS to these events is not known. ISENTRESS should be used with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medication known to cause these conditions.
Additional posters on ISENTRESS presented at CROI
In addition to the STARTMRK study comparing ISENTRESS with efavirenz and the BENCHMRK-1 and -2 studies in treatment-experienced patients with triple-class resistant HIV, two other posters were also presented today further evaluating the safety and efficacy of ISENTRESS. These posters include:
* A review of cancer incidence in ISENTRESS clinical trials in treatment-naïve and treatment-experienced patients, which found to date no difference in the risk of cancer in HIV-infected patients receiving ISENTRESS versus other antiretroviral therapy (Poster 859) and
* A review of preliminary data from an ongoing prospective, open-label, non-randomized, dose finding study of ISENTRESS plus OBT in treatment-experienced children aged 6 to 18 (IMPAACT P1066). These results will be presented by the National Institutes of Health
Review of cancer incidence in ISENTRESS clinical trials
The occurrence of cancer, a known complication of HIV infection, was reviewed in five randomized, double-blind clinical trials of ISENTRESS in treatment-naïve and treatment-experienced patients, as well as an open-label expanded access program. A pooled data analysis of two Phase II (Protocols 004 and 005) and three Phase III trials (BENCHMRK-1, BENCHMRK-2 and STARTMRK) with follow-up of at least 48 to 120 weeks (over 1,700 patient-years exposure to ISENTRESS), found that during the double-blind phase cancer rates were slightly lower for those patients receiving the regimen with ISENTRESS (rate of 1.7 per 100 patient-year, broad cancer case definition, including recurrences, non-melanoma skin cancers and carcinoma in situ) but not significantly different from patients receiving comparator antiretroviral treatments (rate of 2.2 per 100 patient-year, broad cancer definition). This resulted in a relative risk of 0.75 with a confidence interval of 0.40 to 1.46.
With approximately 600 patient-years additional exposure to ISENTRESS during open-label phases, cancer rates remained similar (rate of 2.1 per 100 patient-years) to those observed during the double-blind phase. In an expanded access setting, with median follow-up of 24 weeks for over 5,400 patients (over 2,200 patient-years exposure to ISENTRESS), cancer rates were similar to those observed in clinical trials with ISENTRESS.
In Protocol 004, ISENTRESS was dosed at 100 to 600 mg twice daily up to 48 weeks and then at 400 mg thereafter. In Protocol 005, ISENTRESS was dosed at 200 to 600 mg twice daily until at least 24 weeks in the double-blind portion of the study, and then all were dosed at 400 mg in the open-label portion of the study. The analysis of the Phase II and Phase III trials combined included 1,039 patients who received ISENTRESS and 605 patients who were assigned to a comparator treatment, 173 of whom crossed over from the comparator treatment to ISENTRESS in the open-label phase(s). In all cases, ISENTRESS was used in combination regimens. Data were available through at least 48 weeks in the Phase III STARTMRK trial, 96 weeks in BENCHMRK-1 and BENCHMRK-2 trials and at least 120 weeks in the Phase II trials (Protocols 004 and 005). Double-blind and open-label data were included.
ISENTRESS is the first medicine to be approved in a class of antiretroviral drugs called integrase inhibitors. ISENTRESS works by inhibiting the insertion of HIV-1 DNA into human DNA by the integrase enzyme. Inhibiting integrase from performing this essential function limits the ability of the virus to replicate and infect new cells. There are drugs in use that inhibit two other enzymes critical to the HIV-1 replication process – protease and reverse transcriptase – but ISENTRESS is the only drug approved that inhibits the integrase enzyme.
In October 2007, the U.S. Food and Drug Administration granted ISENTRESS accelerated approval for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients with evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents. ISENTRESS is a single 400 mg tablet taken twice daily without regard to food. During coadministration with rifampin, the recommended dosage of ISENTRESS is 800 mg twice daily with or without food. ISENTRESS does not require boosting with ritonavir.
Merck HIV Research
Merck is committed to developing innovative therapies that offer advances in the treatment of infectious diseases - including HIV. Merck’s efforts to develop investigational treatments for HIV and AIDS have been under way for more than 20 years and continue today. Merck began its HIV integrase inhibitor research in 1993 and was the first to demonstrate inhibition of HIV integrase in vitro and in vivo.
Prevalence of HIV and AIDS
In 2006, more than one million Americans were living with HIV and AIDS, and it is estimated that approximately more than 56,000 new cases of HIV and AIDS are diagnosed each year in the United States.
Worldwide, an estimated 33 million people are infected with HIV and AIDS, and more than two million new infections occurred in 2007.
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